Human pituitary somatotroph adenomas can be associated with mutations of the s alpha-subunit of G proteins. However, the impact of the gsp mutations on the tumoral phenotype is not well understood at present. This study aims to determine whether the detection of this mutation could impact on the management of acromegalic patients. We examined 30 acromegalic patients; 8 were gsp positive, and 22 were gsp negative. The gsp-positive adenomas appeared to secrete significantly more when the ratio of basal GH level/tumor size was considered. A better octreotide sensitivity of mutated adenomas was clearly shown under in vivo (short and long term) and in vitro conditions. During the acute octreotide test, the GH nadir was significantly lower in the gsp-positive adenomas (85% of maximal inhibition vs. 52%). Eighteen patients were treated with octreotide (300 micrograms/day) for at least 3 months before surgery: the percent inhibition of GH hypersecretion was higher in gsp-positive adenomas (76% vs. 47%). In cell culture, the octreotide-induced inhibition of GH release was significantly higher in gsp-positive adenomas (71% vs. 30%). Finally, during 2 yr of postoperative follow-up, GH hypersecretion was controlled in all patients with gsp mutation even in those in whom tumoral tissue remained after surgery. On the contrary, in the gsp-negative group, octreotide treatment was unable to control hypersecretion in 4 patients bearing tumoral remnants. The Gs alpha mutation could, therefore, be a new marker to foresee the susceptibility of the tumor to be controlled by somatostatin analogs, which improves prognosis.